Since the beginning of this project we have screened over 2000 subjects for this study. We have enrolled approximately 130 youth with bipolar disorder (BD), 120 subjects at risk for BD because they have a parent or sibling with the illness, and 100 adults with BD. This year, approximately 20 new subjects were enrolled. This year we continued our work designed to identify the brain mechanisms underlying BD in children; compare brain function in youth and adults with BD in order to begin to understand how the illness develops over time; and compare brain function in youth at familial risk for BD to those with BD and those at low risk, in order to facilitate the eventual development of preventive interventions. In terms of our work on the brain mechanisms mediating BD, much of that work consists of, not only comparing youth with BD to healthy youth, but also comparing youth with BD to those with severe, chronic irritability (the so-called severe mood dysregulation, or SMD, population, see MH002786-07). It is important to compare youth with BD and those with SMD because the latter frequently receive the diagnosis of BD in the community, despite not having a history of manic episodes. This potential misdiagnosis is important from a therapeutic and public health perspective. That is, compared to severe, chronic irritability, BD in youth is both less common and treated with more toxic medications. Therefore, it is important to identify accurately youth with BD and not extend the boundaries of the diagnosis inappropriately. In two published studies, we found that youth with BD, as well as those with SMD, have deficits in amygdala function while viewing emotional faces. In the first study, both patient populations failed to modulate amygdala activity appropriately while viewing angry faces. Specifically, healthy subjects showed increased amygdala activity as the amount of anger on a face increased, while neither of the patient samples did so. This failure to modulate amygdala activity in response to subtle changes in face emotion might be associated with the deficit in face emotion labeling that patients exhibit. Importantly, new data submitted or in preparation for publication indicates a similar deficit in youth at risk for bipolar disorder and in adults with bipolar disorder. This demonstration of a neural deficit present across the developmental spectrum in bipolar disorder, as well as in youth at risk for the illness, suggests that a failure to modulate amygdala activity in response to increased anger on a face may be a biomarker for bipolar disorder. In the second study, both patient populations showed amygdala hyperactivation in response to angry and fearful faces, again showing abnormal amygdala activity in response to face emotions. While the SMD and BD populations did not differ in amygdala activity, they did differ in activity in other brain regions. Specifically, youths with BD showed decreased activation (compared to both SMD and healthy subjects) in anterior cingulate (ACC), insula, and parietal regions while processing angry faces. We are now extending this work to also include youth with attention deficit hyperactivity disorder (ADHD) or anxiety disorders as comparison groups for the youth with BD, in addition to continuing to use youth with chronic severe irritability as a comparison group. We will test the hypothesis that amygdala hyperactivation in response to implicit face emotion processing will be a non-specific deficit present across youth and adults with BD, those at risk for the illness, chronic irritability, and anxiety disorders, but not in non-irritable youth with ADHD. However, we also hypothesize that only the BD phenotypes will show hypoactivation in frontal cortex (specifically, ventro-lateral prefrontal cortex and anterior cingulate cortex). Finally, in a large sample of 181 adults and youth with BD plus matched healthy controls, we attempted to dissociate the impact of face emotion and attentional state (e.g., rating emotion on the face, rating ones own emotion) on neural activity. Pediatric BD rated neutral faces as more hostile than did other groups. In BD adults and youth, we found dysfunction in the amygdala, inferior frontal gyrus (IFG), anterior cingulate cortex (ACC), and putamen. Specifically, patients with BD showed amygdala hyperactivation during explicit processing (hostility ratings) of fearful faces and passive viewing of angry and neutral faces, but IFG hypoactivation during implicit processing of neutral and happy faces. In the ACC and striatum, the direction of dysfunction varied by task demand: BD demonstrated hyperactivation during unconstrained processing of angry or neutral faces, but hypoactivation during constrained processing (implicit or explicit) of angry, neutral, or happy faces. These findings suggest amygdala hyperactivation in BD while processing negatively-valenced and neutral faces, regardless of attentional condition, and BD IFG hypoactivation during implicit processing. In the cognitive control circuit involving the ACC and putamen, BD neural dysfunction was sensitive to task demands. Our work in at risk children continues, in that we are accruing fMRI data on a large sample of children at risk for BD. We have also continued to establish the relationships that would allow us to assess Amish children at risk for BD, and that work is progressing. In addition, we have demonstrated previously behaviorally that children at risk for BD have attentional lapses, as evidenced by increased variability in their response time on motor tasks. We have now devised a sophisticated neuroimaging paradigm to allow us to examine the neural correlates of this deficit, and we have begun to implement it in both children with BD and those at risk for the disorder by virtue of having an affected first-degree relative. In addition, in prior work we demonstrated that, when processing face emotions, youth with BD spent less time focussing on the eyes than did healthy subjects. We are now testing whether that deficit is also present in youth at risk for BD and in adults with BD.